1. Field of the Invention
The present invention relates to a TNF-α production inhibitor containing a kavalactone as an active ingredient, and to a preventive, ameliorating, or therapeutic agent for diseases caused by abnormal production of TNF-α.
2. Background Art
TNF (Tumor Necrosis Factor) was discovered as an antitumor cytokine, and has been elucidated to have carcinostatic activity (i.e., the effect of inhibiting cancer cell growth or necrotizing cancer cells), and to participate in a series of inflammatory responses or immunoreactions, as well as in differentiation or maturation of cells.
Recent studies have shown that excessive production of TNF-α induces onset of a variety of diseases, including cachexia attributed to cancer or infectious diseases (Nature, 316: 552, 1985), septic shock (J. Immunol., 145: 4185, 1990; Science, 229: 869, 1985; Shock, 30: 1990), chronic rheumatoid arthritis (Ann. Rheum. Dis., 49: 665, 1990; Lancet, 344: 1105, 1994; Lancet, 344: 1125, 1994; British J. Rheum., 34: 334, 1995), inflammatory diseases such as ulcerative colitis and Crohn disease (Arch. Dis. Child, 66: 561, 1991; Gastroenterology), osteoarthritis (Arthritis Rheum., 36: 819, 1993), Kawasaki's disease (Clin. Immunol. Immunopathol., 56: 29, 1990), multiple sclerosis (N. Engl. J. Med. , 325(7): 467, 1991), Behchet's disease (J. Rheumatol. , 17: 1107, 1990), systemic lupus erythematosus (STE) (Arthritis Rheum., 32: 146, 1989), rejection during bone marrow transplantation (J. Exp. Med., 175: 405, 1992), multiple organ failure (Rinshoi, 17(20), 2006, 1991), malaria (Science, 237: 1210, 1987), AIDS (J. Acquir. Immune Defic. Syndr., 5: 1099, 1992), meningitis (Lancet, 1: 355, 1987), hepatitis (Kozo Kanno, Kanzo, 33: 213, 1992), and type-II diabetes (Science, 259: 87, 1993).
The aforementioned diseases caused by excessive production of TNF-α have hitherto been treated from a mere palliative approach by use of steroid agents, anti-inflammatory agents, antibiotics, etc., and drugs for fundamentally treating the diseases have not yet been developed.
Kava is a plant found in Fiji and belongs to Piperaceae, Piper L. (nomenclature: Piper Methysticum Forst., alias: Yangona). Since anesthetic beverages are obtained from the kava root, in Oceania, kava is widely cultivated by privileged people and is used in traditional ceremonies or events (Chem. Australia. Oct 377–378 (1987)).
It has been reported that an extract obtained from the dried kava root through extraction with water contains a class of α-pyrone derivatives called kavalactones which induce numbness of the lips or tongue or exert sedative effect, such as methysticin (Chem. Australia. Oct 377–378 (1987), Planta Med. 64 504–506 (1998)).
Studies performed In the University of New South Wales have elucidated that kavalactones exert a sedative effect through a mechanism different from those of other sedative drugs which exert sedative effects when being bound to receptors present in the brain (Planta Med. 65 507–510 (1998)). It has also been reported that kavalactones exert an analgesic effect in a manner different from that of a formulated analgesic drug such as aspirin, and that, unlike morphine, kavalactones are not bound to receptors in the brain (e.g., European Patent Application Laid-Open Nos. 664131 and 523591, and Japanese Kohyo (PCT) Patent Publication No. 5-502457).
It has also been reported that kava extract exerts an antibacterial effect and is useful for treating Helicobacter pylori infection (German Patent Application Laid-Open No. 19716660), and that the kava extract exerts a neuroprotective effect and is useful for treating brain dysfunction, Alzheimer's disease, brain injury, etc. (e.g., European Patent Application Laid-Open No. 523591, and Japanese Kohyo (PCT) Patent Publication No. 5-502457).
However, until the present invention was attained, kavalactones and kava extract have not been known to exert the effect of inhibiting TNF-α production.